3-Hydroxyacyl aminomethyl-5-acylamino-2,4,6-triiodobenzoic acid salts as x-ray contrast agents

ABSTRACT

The water-soluble, physiologically tolerated sodium and alkanolamine salts of 3-hydroxyacylaminomethyl-5-acylamino-2,4,6triiodobenzoic acids of the formula WHEREIN R and R&#39;&#39;&#39;&#39; are hydrogen or methyl, R&#39;&#39; is hydrogen or hydroxy, R&#39;&#39; is hydroxyl when R is hydrogen, and R&#39;&#39;&#39;&#39; is hydrogen when R&#39;&#39; is hydrogen, are X-ray contrast agents suitable for urography and vasography and well tolerated when their aqueous solutions are injected into a vein.

United States Patent [1 1 Felder et al.

1 May 27, 1975 l l 3-HYDROXYACYL AMINOMETHYL-S-ACYLAMIN()-2,4,6- TRIIODOBENZOIC ACID SALTS AS X-RAY CONTRAST AGENTS [75] Inventors: Ernst Felder; Davide Pitre, both of Milan Italy [73] Assignee: Bracco Industria Chimica, Societa per Axioni, Milan, Italy 221 Filed: June 24, 1974 211 App|.No.:482,666

[30] Foreign Application Priority Data July 17, 1973 Switzerland 1. lO449/73 [52} US. Cl..... 260/501.11; 260/211 R; 260/471 C;

260/488 CD; 260/518 A; 260/519; 424/5 [51] Int. Cl. C07c 103/32 [58] Field of Search 260/501.l l, 519

[56] References Cited UNITED STATES PATENTS 3,622,616 ll/l97l Guerbet et a] 260/519 Primary [i.\an1inerRobert Robert Gerstl Assistant E.\'amt'nerL. Arnold Thaxton Attorney, Agent, or Firm-Hans Berman; Kurt Kelman [57] ABSTRACT The water-soluble, physiologically tolerated sodium and alkanolamine salts of 3-hydroxyacylaminomethyl- 5-acylamino-2,4,6-triiodobenzoic acids of the formula 7 Claims, No lDrawings 3-HYDROXYACYL AMlNOMETHYL-S-ACYLAMlNO-2,4,6- TRIIODOBENZOIC ACID SALTS AS X-RAY CONTRAST AGENTS This invention relates to contrast agents for radiography, and particularly to radiopaque compounds whose sodium and alkanolamine salts are freely soluble in water and well tolerated when their aqueous solutions are administered intravenously prior to urography or vasography, to the preparation of the compounds, to the injectable compositions containing their salts, and to the use of the compositions in radiography.

lt has been found that the aqueous solutions of sodium salts and alkanolamine salts of 3- hydroxyacylaminomethyl-5-acylamino-2,4,6 triiodobenzoic acids of the formula coon R" I ,T --1 a i t\ i R ca co NH crater co car on (I) wherein R and R" are hydrogen or methyl, R is hydrogen or hydroxyl, R is hydroxyl when R is hydrogen, and R" is hydrogen when R is hydrogen, are well tolerated when injected intravenously into a body in which a cavity is to be made opaque to X-rays, particularly for urography or vasography.

The five compounds encompassed by the above for mula will be referred to hereinafter by capital letters as follows:

A: 3-04-Hydroxypropionylaminomethyl-S- hydroxyacetylamino-2,4,6-triiodobenzoic acid B: 3-a-Hydroxypropionylaminomethyl-i acetylamino-Z,4,6-triiodobenzoic acid C: 3-ot-Hydroxypropionlyaminomethyl-S-ahydroxypropionylamino-Z,4,6-triiodobenzoic acid 3Hydroxyacetylaminomethyl-S- hydroxyacetylaminoQ,4,6-triiodobenzoic acid 3-Hydroxyacetylaminomethyl-5ahydroxypropionylamino-Z,4,6-triiodobenzoic acid.

The watersoluhle salts of these compounds are preferentially excreted with the urine by the kidneys, making them suitable for urography as well as vasography. They are superior in their low toxicity to the structurally most closely related known compounds as well as to the best contrast agents for urography and vasography in common clinical use heretofore.

Toxicity and excretion data of typical compounds of the invention are listed in Table l together with corresponding data for the following known compounds:

l: 3-Acetylaminomcthyl-5-hydroxyaectylamino- 2,4,6-triiodobenzoic acid (German patent appliation No. 2,124,904, published Dec 7, i972) 3-Acctylaminomethyl-S-acetylamino-Z.41- triiodobenzoic acid (l()DAMlDF.; Swiss Pat. No.

414.063 L; 3,5-His(-acctylamino)-l-Lo-triiodobenzoic acid (ANHDOTRIZOATE; Swiss Pat. Nos. 332.648 and -male white mice and is reported in mg iodine per kg body weight. The excretion data were derived from tests on anesthetized rabbits carrying catheters in their ureters. The secreted urine was analyzed for iodine content by means of an automatic analyzer, and the percentage of iodine excreted within 3 hours after injection of 100 mg iodine per kg body weight was calculated from the analytical data.

TABLE I COMPOUND Toxicity Excretion miJflg [/kg ,after 3 hrs E (Na-salt) 8900 80 The water-soluble, physiologically tolerated sodium and alkanolamine salts of the: compounds of the invention are administered intravenously by injection or infusion for urography and vasography. The mono-, di- ,and polyhydroxyalkylamines commonly employed in pharmacy as catinic moieties in injectable salts with physiologically active acids are generally suitable for the purpose of this invention. They include, but are not limited to, N-methyl-D-glucamine, N-methylxyalmine( l-methylamino-l -desoxy-D-xylite lmethylamino'2,3-propanediol, diethanolamine, monocthanolamine. and tris-(hydroxymethyl)- aminomethane. Mixtures of sodium and alkanolamine salts are preferred in preparing aqueous compositions of high iodine content for optimum tolerance and low viscosity of the injected solutions. The choice of the cationic moiety or moieties may also be influenced by the specific application, as is known in itself. For intravenous injection, solutions containing mg to 450 mg iodine per milliliter are generally preferred, but the salts lend themselves readily to the preparation of aqueous compositions containing more than 500 ml iodine per milliliter, as may sometimes be necessary. For intravenous infusion. more dilute solutions containing 45 to 150 mg iodine per milliliter are normally employed.

In preparing the compounds of formula (I), 3- aminomethyl-S-amino-2,4,o'triiodobenzoic acid is reacted with one of two aeylating agents which are acids of the respective formulas and i i rz -ctr-cooa R -cn cooa 2 (III) tion of an ether group, and readily saponifiable halogen, R is hydrogen or a masking radical of said group. R and R" are hydrogen or methyl, the acids being combined with a dehydrating agent, or which are anhydrides or acyl halides of the respective acids of formulas (ll) and (lll) until an intermediate is formed in which one of the amino groups of the 3-aminomethyl- S-amino-Z,4,6-triiodobenzoic acid is acylated. The intermediate then is reacted with the other one of the acylating agents, and the compound of formula (I) is recovered from the reaction mixture while all masking radicals present are removed by hydrolysis or hydrogenolysis, preferably by hydrolysis in an alkaline aqueous medium at moderately elevated temperature.

The preferred acylating agents are the halides. particularly the chlorides, and the anhydrides of the carboxylic acids of formulas (ll) and (Ill).

When R, and R are identical, the two acylation reactions outlined above are conveniently combined in a single step without isolating the intermediate. The 3- aminomethyl group of the starting material is more reactive than the aromatic S-amino group and is normally acylated first.

For introducing hydroxyacylamino groups in the starting material, it is essential that hydroxy groups in the acylating agents of formulas (II) and (Ill), and in the corresponding acyl halides or anhdrides, be masked as by esterification with a carboxylic acid or hydrogen halide, or by ether formation with a group that is readily split off. Preferred ester forming radicals are the acyloxy groups of lower alkanoic acids, such as the acetyloxy group. However, the acyloxy groups of araliphatic or aromatic acids are equally effective.

The acyloxy group masking a hydroxyl group in a compound of formula (I) is readily removed during recovery of the desired compound by alkaline hydrolysis without requiring a separate operation. During acylation of tri-iodated aromatic amines, particularly during acylation by means of carboxylic acid anhydrides, both hydrogen atoms of the aromatic nitrogen in position 5 are often acylated. The N-diacyl derivatives are not very stable, and one acyl group is readily split off during alkaline hydrolysis under mild conditions. These conditions also cause simultaneous hydrolysis of acyloxy groups which may be present in the molecule. The hydrolyzation reactions are readily performed at a pH of 9 to 12 at temperatures between and 60C, sodium hydroxide being a convenient hydrolyzing agent. and are represented by the following equations:

acyl

m N301 acyl N ROI-I [IO-LH-CO-N: acyl-Okla wherein acyl may be acetyl. for examp e.

For masking, the hydrogen atom in the hydroxyl group to be masked may also be replaced by a benzyl. diphenylmethyl. triphenylmethyl (trityl). trimethylsilyl or similar group forming an ether which is readily split without simultaneously affecting the amide bond. Lltimately, the hydroxyl group may also be replaced for masking purposes by halogen. more specifically chlorine, bromine, or iodine. which is removed during recovery of the end product by alkaline saponification in a manner obvious from the above equations.

The sequence in which the two available amino groups of 3-aminomethyl-5-amino-2.4.6- triiodobenzoic acid are acylated may be modified by first preparing a 3-amino-methyl-5-acylamino-2,4,6- triiodobenzoic acid in which subsequently the 3- aminomethyl group is acylated by reaction with a carboxylic acid of formula (ll) or its acyl halide or anhydride. This procedure generally is not preferred because it requires initial masking of the 3-aminomethyl group by a selectively removable group such as urethanyl group or ureido group, as will be shown in more detail hereinbelow in Example 5, the starting material being thus of the formula wherein R is hydrogen, COO Alkyl, COO Aralkyl, or CONH The following Examples are further illustrative of this invention. The R,values reported in the Examples were determined by thin layer chromatography (TLC) on silica gel using a solvent system of methylethylketone/- glacial acetic acid/50% ethanol 201316 unless stated otherwise.

EXAMPLE l 3-a-Hydroxypropionylaminomethyl5- hydroxyacetylamino-2,4,6-triiodobenzoic acid (Compound A) 55.4 g (0.1 Mole) 3-aminomethyl-5-amino-2.4.6- triiodobenzoic acid(Helv. Chim. Acta 48 [1965] 259) was dissolved in 200 ml water and ml l-N sodium hydroxide solution. The solution was cooled with ice while a solution of 15 g Z-acetoxypropionyl chloride (0.l mole) in 30 ml acetone and 100 ml l-N sodium hydroxide solution were added simultaneously drop by drop. After the reaction was completed. the pH of the mixture dropped to 5. and 11.5 g unreacted 3- aminomethyl-5-amino-2,4.6-triiodobenzoic acid was precipitated gradually. It was recovered by filtering after l6 hours, and the filtrate was made strongly acid by addition of hydrochloric acid to precipitate 46 g 3- a-acetoxypropionyl-aminomethyl-S-amino-2.4,6- triiodobenzoic acid which melted with decomposition at 203 to 204C, and gave an R value of 0.89. The yield was 89% based on the actually reacted triiodobenzoic acid derivative. The intermediate was identified by elementary analysis.

solved in 30 ml dimethylformamide. and 5.4 g acetoxyaeetylchloride was added to the solution drop by drop with ice cooling. The mixture was stirred 4 hours at 6 room temperature and then evaporated t dryness i a turbidity, and the filtrate was acidified with 18% hydro vacuum. The residue was stirred with 200 ml water, Chloric acid The Precipitated Crude and filtered off. It was dissolved in dilute sodium hy y yp P Y Y B fi droxide solution, and the solution so obtained was triiodobenloic acid was eco ered in an amount of 31 heated to 50C and kept at pH by additions of l-N 5 Y y filtration with Suction and had a melt- NaOH. When the pH stabilized, the solution was acidig P of to fied with dilute hydrochloric acid and evaporated to It was diSSOll/ed in 50 ml boiling methanol, whereby dryness in a vacuum. The residue was taken up in 150 115 Crystal form w Changed and P ml ethanol permitting the removal of undissolved soy yp p y y y 0- dium chloride and some sodium acetate by filtration. 10 triiodobenzoic acid was Precipitated graduilny- It The alcoholic filtrate was evaporated to dryness, and weighed g. at 2620;265OC n), and

the residue was taken up in 30 ml boiling water, 9.7 g gave an R, value of 0.60.

Calcd for c jxH glaNgosi 23.7371. C; 57.8671. 1; eq.wt. 658. Found: 2362 57.6371. 1; eq.wt. 668.

3-a-Hydroxypropiony]amin methyI-S- The free acid is only sparingly soluble in water, methhydroxyacetylamino-2.4.6-triiodobenzoic acid crystal 21110 h nOL r hl roform at the respective boiling lized upon cooling. It had a melting point of temperatures. The sodium and N-methylglucamine 166l68C, and gave an R, value of 0.48. salts dissolve at 20C in an equal weight of water or It was identified by elementary analysis and equivaless.

lent weight:

EXAMPLE 3 i 3-a-Hydroxypropionylarninomethyl-S-otgii niif gidi i ii 22.55%. c; 54.8372 1; :2. vt. 638 hydroxypropronylammo-Z,4,6-trnodobenzoic acid (Compound C) The pure acid is only sparingly soluble in water, even 10.8 g 3-Aminomethyl-5-amin0-2,4,6-triiodobenzoic at moderately elevated temperature, and in chloro- 3O acid (0.02 mole) was suspended in ml dimethylform. It dissolves readily in methanol and less readily formamide, and 15 g 2-acetoxypropionyl chloride (0.1 in ethanol. The sodium and N-methylglucamine salts mole) was added drop by drop while the mixture was dissolve in an equal weight of water or less at 20C. being stirred and cooled with ice. After 15 hours, the

solution so obtained was evaporated to dryness in a EXAMPLE 2 vacuum. The residue was extracted with 150 ml water, 3-a-Hydroxypropionylaminomethyl-S-acetylaminoand the extract was removed by filtering with suction.

2.4.6-t1' d nZ acid (C P The solid residue was dissolved in 50 ml water by gradual addition of sodium bicarbonate, the solution was filtered, and the filtrate was acidified with hydrochloric 4O acid.

The precipitate formed was dissolved in water by ad dition of 2-N sodium hydroxide solution, and the solution was kept at 60C while a pH of 10 was maintained 46.1 g (0.07 Mole) 3-a-acetoxypropionylaminomethyl-5-amino-2.4,6-triiodobenzoic acid prepared as in Example 1 was acetylated by heating for 3 hours on a steam bath with 20 ml acetic anhydride in 100 m1 acetic acid in the presence of 0.1 ml sulfuric acid. Upon cooling of the reaction mixture, 3-aacetoxypmpionybarninomethYLS acetylamino z 476 by dropwise additions of 2-N sodium nydrox1de until triiodobenzoic acid crystallized and was recovered in the i i grouPs had been P Off- After Coolmg, the an amount of 35.3 g (71% yield). 1t melted at 245 (desaporllficailon was mlxed Wl mough hydro Comp) and gavg an Rf valuc of 0075 chloric acid to make it strongly acidic, whereby a precipitate was formed. The liquid was evaporated to dry ness in a vacuum without removing the precipitate, and the residue was dried carefully. It was then extracted Calculated for c,,,a, .,i .,rv.,o..; 25.7w. c; 54.3w. 1. with absolute filhanoh Permitting the removal 0f undis- Found: 25.57%. C; 54.50%.1. solved sodium chloride and sodium acetate by filtration. The liquid extract was evaporated in a vacuum. The residue melted at 120130C. 35.3 g 3a-Acetoxypropi yly It was taken up in 20 ml boiling ethyl acetate from acetylamino-2,4,6-triiodobenzoic acid was dissolved in hi h pure 3 -h d i l i p5- a mixture of 50 ml l-N sodium hydroxide solution and hydroxypmphmylumhlOQabhhodohcnzoic acid 100 ml water, and the solution was kept at 50C until crysmhized upon Cooling h melted at 245 w the a-acetoxy groups were completely saponified. a pH Comp) dhd gave an value f 053 i methyl;

of 10 being maintained by father additions of l-N so- (,0 thylkcwne/glucidl acetic 50o, ethanol 501316- Calcd for H l N Q z 24.4-1' 55.34" 1: etrwt. 688. Found: 24.35 55.439. 1; et wt. 684.

. dium hvdroxide as needed. After the saponification Saturated solutions of the tree acid in water at 20C mixture was adjusted to pH 5 with hydrochloric acid. contain 15?. those in boiling water 47/. and a solution it was treated with active carbon and filtered to remove in ethanol at 20C 20% of the compound.

EXAMPLE 4 3-Hydroxyacetylaminomethyl-5hydroxyacetylamino- 2.4,6-triiodobenzoic acid (Compound D) A suspension of 21.72 g (0.04 mole) 3-aminomethyl- -amino-2,4,6-triiodobenzoic acid in 80 ml dimethylacetamide was mixed over a period of 25 minutes with 27.2 g acetoxyacetyl chloride (0.2 mole) with stirring at 0C. The temperature was permitted gradually to rise to room temperature, and stirring was continued for 13 hours. The solution then was poured into 400 ml water, and the precipitate formed thereby was filtered off with suction, washed with water, and taken up in dilute sodium hydroxide. The solution was adjusted to pH 6 and filtered to remove turbidity. The filtrate was adjusted to pH 9.5 with sodium hydroxide and heated to 55C. A pH of 9.5 was maintained by gradual addition of 80 ml l-N sodium hydroxide. When the pH became stable (about l2 hours), the solution was cooled to ambient temperature and acidified with hydrochloric acid.

The precipitated Compound C weighing 22.2 g (84.2% yield) was further purified by dissolution in dilute sodium hydroxide and precipitation with hydrochloric acid. It had a melting point of l88l89C and gave an R, value of 0.4 with a solvent system of butanol/glacial acetic acid/water 3: l :2. lt absorbs two moles of crystal water from a moist ambient atmosphere.

67.8 g Intermediate 1 (0.1 mole), prepared as described above. was mixed with 120 ml glacial acetic acid, ml acetic anhydride, and 0.1 ml concentrated sulfuric acid, and the mixture was stirred on a steam bath for 3 hours. All ingredients initially present dissolved, and 3-benzyloxycarbonylaminomethyl-5- acetylamino-2,4,6-triiodobenzoic acid (Intermediate 2) then precipitated in an amount of 60 g (84% yield). The recovered lntermediate 2 melted at 210 to 215C.

Calculated for CMHWLNQOS: 30.02%, C: 52.87%. 1. Found: 29.99%, C; 52.9171. 1.

19.3 g Intermediate 2 was added in small batches to Calcd for C H I N O 21.84%. C; Found: 21.98%. C;

eq.wt. 659.94. eq.wt. 655, 665.

Found:

7.14%. H2O 7.01%, H2O

At 20C, water dissolves 2%, methanol and ethanol 50% of the free acid. Water at 96Cdissolves20%. The

EXAMPLE 5 3-a-Hydroxypropionylaminomethyl-5-acetylamino- 2,4,6-triiodobenzoic acid Compound B was also prepared by an alternative method.

54.3 g Aminomethyl-S-amino-2,4,6triiodobenzoic acid (0.1 mole) was suspended in 500 ml water and dissolved by the addition of 100 ml l.0-l l sodium hydroxide. While the solution was stirred at 510C, 40 ml of a toluene solution of benzyl chloroformate (0.1 1 mole) and 100 ml l-N sodium hydroxide solution were added simultaneously drop by drop in such a manner as to maintain a pH of 10 to 11 in the mixture. The so lution so obtained was adjusted to pH 7 and extracted with ethyl ether. When the aqueous phase was acidified, 55.4 g 3-benzyloxycarbonylaminomethyl-S- amino-2,4,6-triiodobenzoic acid (82% yield, Intermediate l) was precipitated. The precipitate crystallized spontaneously upon contact with hot acetic acid. had a melting point of 205 to 208C. and was identified by analysis:

Found:

8.8 g (0.015 Mole) Intermediate 3 was suspended in 30 ml dimethylformamide, and 10 ml solvent was distilled off in a vacuum to remove all moisture. 4.5 g (0.03 Mole) a-acetoxypropionyl chloride in 10 m1 dimethylformamide was added dropwise with stirring, stirring was continued 20 hours at room temperature, and the reaction mixture was then evaporated to dryness in a vacuum. The residue was triturated with water, filtered out with suction, and dissolved in ml water and 2-N sodium hydroxide solution. The solution so formed was kept at 50C and at a pH of 10 by continuous small additions of l-N sodium hydroxide solution until the acetoxy groups were completely saponified.

Compound B then was precipitated with hydrochloric acid and purified as described in Example 2. It was recovered in an amount of 8 g (81% yield) and had an equivalent weight of 667 (calculated: 658).

EXAMPLE 6 3-Hydroxyacetylaminomethyl-S-hydroxyacetylamino- 2.4.6-triiodobenzoic acid (Compound D) When 0.1 mole 3-aminomethyl-5-amino-2,4.6- triiodobenzoic acid was reacted with 0.3 mole chloro acetyl chloride in dimethylacetamidc at 010C. 3- chloroacetylaminomethyl-5-chloroacetylamino-Z,4,6- triiodobenzoic acid was obtained. This compound when stored in water containing at least 3 moles sodium hydroxide per mole of the benzoic acid derivative at 2050C was saponified to Compound D which EXAMPLE 7 3-H ydroxyacetylaminomethyl-5-cthydroxypropionylamino-2.4.6-triiodobenzoic acid (Compound E) 108 g (0.2 Mole) 3-aminomethyl-5-amino-2.4,6-

triiodobenzoic acid was suspended in 400 ml water. 1

and a clear solution was formed when 200 ml l.0-N sodium hydroxide solution was added. Over a period of l hour, a solution of 27.3 g (0.2 mole) acetoxyacetyl chloride in 60 ml acetone and aproximately 210 ml l-N sodium hydroxide solution were added dropwise simultaneously with stirring and ice cooling at such a rate that a pH of to 10.5 was maintained. After all ingredients were combined, the mixture was further stirred 2 hours at l0 to C and a pH of l0 to l0.5.

Thereafter, the pH of the mixture was adjusted to 5. and stirring was continued for 2 hours. A small amount of starting material precipitated and was filtered off.

Found:

kept at 50C. and a pH of 10 was maintained by further additions of l5 /t sodium hydroxide until the acetoxy groups were completely saponified. The solution then was acidified with l87r hydrochloric acid which did not produce a precipitatev The acidic solution was evaporated to dryness in a vacuum, and the residue was dis solved in approximately one liter absolute ethanol except for sodium chloride which was removed by filtering. The filtrate was again evaporated to dryness, and the semisolid residue was suspended in 200 ml ethanol. g N.N-Dimethyl-cyclohexylamine was added, and the mixture was stirred three hours at room temperature, thereafter 5 hours longer at about 0C.

The precipitated cyclohexylamine salt weighing 74 g was filtered off with suction. 70 g (0.086 Mole) of the salt was suspended in water, and brought into solution by adding about 90 ml l-N sodium hydroxide. The solution so obtained was evaporated to dryness in a vacuum. The residue was dissolved in water. the solution was made strongly acidic with hydrochloric acid and again evaporated to dryness. The residue was taken up in hot. anhydrous ethanol. The undissolved sodium chloride was filtered off. and the filtrate was evaporated to dryness. The residue was suspended in water from which Compound E precipitated in crystals weighing 35 g and melting at 240 to 242C. It gave an R, value of 0.495.

eq.wt. 674.

The filtrate was strongly acidified, and the precipitate The sodium and Nmethylglucamine salts dissolve very readily in water.

EXAMPLE 8 X-Ray contrast compositions for use in urography or vasography were prepared according to the formulations in Table ll.

Calcd for C H I N O 22 3X/( C; 59.] W1. l; eq.wt. 643.94. Found: 22,37'.-; C; 59.08%. I; eq.wt. 645.8.

TABLE ll Compound D, g 20 Compound B (Ex. 2). g 778 Compound C. g 772.5 Compound A. g 31g N-Methylglucamine. g I I4 9 133 2 97.61 N-Methyhxylamine. g 54.5 Monoethanolamine. g 24.42 30.54 l-Methylamino 2.lpropanediol. g 34.7 Sodium hydroxide. g 8.0 l3.2 7.32 Tris-thydroxymethyll-aminomethane. g l2.l l 7.26 Disodium EDTA. g 0.l ().l ().l Water to make ml 1000 l200 1000 l000 lodinc content. mg/ml 300 375 400 450 l09.5 g 3-Acetoxyacetylaminomethyl-S-amino- 2,4.6-triiodobenzoic acid was dissoived in 255 ml dimethylformamide. and the solution was stirred at l0 to 15C while 51 g a-acetoxypropionyl chloride was added dropwise. After a few hours stirring at room temperature. the reaction solution was evaporated to dryness in a vacuum. the residue was di l d in a little actone. and the acetone solution was stirred into one liter water.

A gummy precipitate formed and was dissolved in ml 1554 sodium hydroxide solution. The solution was The disodium ethylenediarnine tetraacetic acid was first dissolved in a small amount of bidistilled water. and the other solid ingredients were then added with stirring. The solution so obtained was adjusted to pH 7.1 i 0.2. filtered. and diluted with bidistilled water to the volume indicated. The diluted solution was distributed in glass vials of l0 and 20 ml capacity which were sealed in a nitrogen atmosphere and heated to l l0l 20C for about 20 minutes for sterilization of the contents.

wherein R and R" are hydrogen or methyl, R is hydrogen or hydroxyl, R is hydroxyl when R is hydrogen, and

R is hydrogen when R is hydrogen; or a water-soluble, physiologically tolerated sodium or alkanolamine salt of said acid.

2. A compound as set forth in claim 1. wherein R is hydrogen.

3. A compound as set forth in claim 2, wherein R is hydrogen.

4. A compound as set forth in claim 2, wherein R" is methyl.

5. A compound as set forth in claim l, wherein R is methyl. and R is hydrogen.

6. A compound as set forth in claim 1, wherein R is methyl. R is hydroxyl. and R" is hydrogen.

7. A compound as set forth in claim 1. wherein R and 

1. A COMPOUND WHICH IS A 3-HYDROXACYLAMINOMETHYL-5ACYLAMINO-2,4,6-TRIIODOBENZOIC ACID OF THE FORMULA
 2. A compound as set forth in claim 1, wherein R is hydrogen.
 3. A compound as set forth in claim 2, wherein R'''' is hydrogen.
 4. A compound as set forth in claim 2, wherein R'''' is methyl.
 5. A compound as set forth in claim 1, wherein R is methyl, and R'' is hydrogen.
 6. A compound as set forth in claim 1, wherein R is methyl, R'' is hydroxyl, and R'''' is hydrogen.
 7. A compound as set forth in claim 1, wherein R and R'''' are methyl. 